LETTER TO JMG

The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening

C Thauvin-Robinet^1,3, A Munck^2,3,4, F Huet^2,3,5, E Génin⁶, G Bellis⁷, E Gautier⁸, M-P Audrézet^9,10, C Férec^9,10, G Lalau^9,11, M Des Georges^9,12, M Claustres^9,12, T Bienvenu^9,13, B Gérard^9,14, P Boisseau^9,15, F Cabet-Bey^9,16, D Feldmann^9,17, C Clavel^9,18, E Bieth^9,19, A Iron^9,20, B Simon-Bouy^9,21, C Costa^9,22, R Medina²², J Leclerc^9,11, D Hubert^3,23, R Nové-Josserand^3,24, I Sermet-Gaudelus^3,25, G Rault^3,26, J Flori²⁷, S Leroy^3,28, N Wizla^3,29, G Bellon^3,30, A Haloun^3,31, S Perez-Martin^3,5, G d’Acremont^3,32, H Corvol^3,33, A Clément^3,33, E Houssin², C Binquet⁸, C Bonithon-Kopp⁸, C Alberti-Boulmé³⁴, M A Morris³⁵, L Faivre¹, M Goossens^9,22, M Roussey^2,3,36, the Collaborating Working Group on R117H and E Girodon^9,22

¹ Centre de Génétique, Hôpital d’Enfants, CHU de Dijon, Dijon, France
² AFDPHE, Paris, France
³ French CF Care Centres, France
⁴ CRCM - Service de gastro-entérologie-mucoviscidose et nutrition pédiatriques, Hôpital Robert Debré, APHP, Paris, France
⁵ CRCM – Service de Pédiatrie 1, Hôpital d’Enfants, CHU Dijon, Dijon, France
⁶ Inserm U794 et Fondation Jean Dausset/CEPH, Paris, France
⁷ INED, Paris, France
⁸ Unité INSERM U866 CIE1, Faculté de médecine de Dijon, CHU Dijon, Dijon, France
⁹ French CF Laboratory Network, France
¹⁰ Laboratoire de Génétique Moléculaire et d’Histocompatibilité, CHU de Brest, Brest, France
¹¹ Pôle de Biochimie et Biologie Moléculaire, Centre de Biologie Pathologie, CHU de Lille, Lille, France
¹² Laboratoire de Génétique Moléculaire, IURC, CHU de Montpellier, Montpellier, France
¹³ Laboratoire de Biochimie-Génétique, Hôpital Cochin, APHP, Paris, France
¹⁴ Laboratoire de Biochimie Génétique, Hôpital Robert Debré, APHP, Paris, France
¹⁵ Service de Génétique Médicale, Laboratoire de Génétique Moléculaire, CHU Hôtel Dieu, Nantes, France
¹⁶ Service d’Endocrinologie Moléculaire et Maladies rares, Centre de Biologie et Pathologie Est, CHU de Lyon, Bron, France
¹⁷ Laboratoire de Biochimie et Biologie Moléculaire, Hôpital d’Enfants Armand Trousseau, APHP, Paris, France
¹⁸ Laboratoire Pol Bouin, UF Biologie Cellulaire, Hôpital de la Maison Blanche, CHU de Reims, Reims, France
¹⁹ Service de Génétique Médicale, Hôpital Purpan, CHU de Toulouse, Toulouse, France
²⁰ Laboratoire de Génétique Moléculaire, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Bordeaux, France
²¹ Laboratoire SESEP, Centre hospitalier de Versailles, Le Chesnay, France
²² Service de Biochimie-Génétique et Inserm U955 équipe 11, Groupe Henri Mondor-Albert Chenevier, APHP, Créteil, France
²³ CRCM - Service de Pneumologie, Hôpital Cochin, APHP, Paris, France
²⁴ CRCM - Service de Médecine interne, Centre hospitalier Lyon sud, Pierre-Bénite, France
²⁵ CRCM - Service de Pédiatrie générale, Hôpital Necker-Enfants-Malades, APHP, Paris, France
²⁶ CRCM - Centre de Perharidy, Roscoff, France
²⁷ Service de Néonatologie, SIHCUS – CMCO, Schiltigheim, France
²⁸ CRCM - Service de pneumologie et immunoallergologie, CHRU de Lille, Lille, France
²⁹ CRCM - Clinique de pédiatrie, CHRU de Lille, Lille, France
³⁰ CRCM Lyon Pédiatrie, Groupement Hospitalier Lyon Est, Bron, France
³¹ CRCM - Unité de transplantation thoracique, CHU Hôpital Guillaume et René Laënnec, Nantes, France
³² CRCM - Service de Pédiatrie, CHI de Créteil, France
³³ CRCM - Service de pneumologie pédiatrique, Hôpital d’Enfants Armand-Trousseau, APHP, Paris, France
³⁴ Centre d’Epidémiologie Clinique, Hôpital Robert Debré, APHP, Paris, France
³⁵ Laboratoire de Diagnostic moléculaire, Service de Médecine Génétique, Hôpitaux Universitaires, Geneva, Switzerland
³⁶ CRCM - Département de médecine de l’enfant et de l’adolescent, CHU de Rennes - Hôpital Sud, Rennes, France

^{Correspondence to} Dr C Thauvin-Robinet, Centre de Génétique, Hôpital d’Enfants, 10, bd Maréchal de Lattre de Tassigny, BP 77 908, 21079 Dijon cedex, France; christel.thauvin{at}chu-dijon.fr

Background: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice.

Methods: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p_R117H), on either intron 8 T5 or T7 background, and F508del (p_F508del) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype.

Results: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults’ severe pulmonary symptoms. In 5245 healthy adults, p_F508del was 1.06%, p_R117H;T7 0.27% and p_R117H;T5<0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%.

Conclusions: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes.

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